Sustained release formulations for the treatment of intraocular pressure or glaucoma

ABSTRACT

The present embodiments provide for methods of treating elevated intraocular pressure or glaucoma using a sustained release medicament consisting of prostaglandin in benzyl benzoate that is injected intraocularly no more frequently than once every two months.

RELATED APPLICATION

This application is a continuation of application Ser. No. 14/168,139,filed Jan. 30, 2014, which claims priority benefit of U.S. ApplicationNo. 61/759,129, filed Jan. 31, 2013, which is incorporated fully hereinby reference.

BACKGROUND

Glaucoma is a leading cause of blindness in the world, and is commonlycharacterized by progressive optic neuropathy with associated visualfield deficits. Estimates put the total number of suspected cases ofglaucoma at over 70 million worldwide. Everyone is at risk for glaucoma,regardless of age: even though older people are at a higher risk forglaucoma, infants and children can suffer from glaucoma. High-riskgroups include people over 60, family members of those alreadydiagnosed, and people who are severely nearsighted.

Glaucoma usually results from fluid pressure building inside the eyeuntil the optic nerve becomes damaged, leading to progressive,irreversible vision loss. The two main types of glaucoma are primaryopen-angle glaucoma and angle-closure glaucoma. Primary open-angleglaucoma causes 90% of glaucoma cases; its symptoms may include a lossof peripheral vision or tunnel vision. Symptoms of acute angle-closureglaucoma may include eye pain, blurred vision, nausea and/or vomiting,eye redness and seeing halos around lights. There are also low-tensionor normal-tension forms, and congenital, pigmentary, andpseudoexfoliation forms of glaucoma. Secondary glaucoma can also developas a complication from other medical conditions.

Although once sight is lost it cannot be recovered, it is possible, withtreatment, to halt further vision loss caused by glaucoma. Glaucomatreatments include medicines, laser trabeculoplasty, conventionalsurgery, or a combination of any of these. Glaucoma medicines need to betaken regularly, and some medicines can cause headaches or other sideeffects. For example, drops may cause stinging, burning, and redness inthe eyes. Because glaucoma often has no symptoms, people are oftentempted to stop taking, or may forget to take, medicine. Compliance witheye drops regimens is especially problematic for the elderly. Thereremains a need for sustained release formulations for deliveringglaucoma treatments.

SUMMARY

The embodiments described herein provide for sustained releasepharmaceutical formulations for treatment of high intraocular pressureand glaucoma. More specifically, formulations consisting of aprostaglandin in a benzyl benzoate can be injected into the vitreous ofthe eye, where sustained release of prostaglandin lasts for at least twomonths, lowering intraocular pressure and maintaining that lowerpressure. In an alternative embodiment, the formulation can be injecteddirectly into the anterior chamber of the eye. Indeed, kinetic studieshave demonstrated that particular formulations of latanoprost in benzylbenzoate can provide for sustained release of latanoprost for over sixmonths with a single intraocular injection.

The length of time over which the release of the prostaglandin issustained correlates with the concentration of prostaglandin in theformulation: higher concentrations of prostaglandin provide for longersustained release. The length of time over which the release of theprostaglandin is sustained also correlates with the size of the doseadministered: a larger dosage unit (volume) provides for a longersustained release of active agent. The unit dose volume for intravitrealinjection (or injection into the anterior chamber) typically ranges fromabout 5 μL to about 100 μL, more typically from about 5 μL to about 60μL. The typical range of prostaglandin in the formulation ranges from0.1% to 5% (w/w). Thus, the practitioner can select a formulation basedon concentration of drug in the formulation, the size of the unitdosage, or both, to deliver prostaglandin for a desired length of time.This also allows a dosing regimen in which the re-administration of theformulation can be determined by considering the patient's needs, thesustained release profile of the formulation, and the therapeutic effectobserved by the physician. For example, a patient can receive aninjection about every 60 days (two months), 90 days (three months), 120days (four months), or as the physician directs. Typically, intraocularinjections (into the anterior chamber or vitreous) of theprostaglandin/benzyl benzoate formulations described herein areadministered no more frequently than once every two months, once everythree months, once every four months, etc., to once every twelve months.An example treatment schedule for a human patient comprises of oneintravitreal injection of about 25 μL of a formulation consisting solelyof 0.1% to 1% (w/w) latanoprost in benzyl benzoate, which may berepeated no more frequently than once every two months. Additionally,the pharmacological effect may last beyond the disappearance of thedosage form.

When administered into the eye via intravitreal injection, thesubstantially clear, liquid formulation maintains a monolithic form(e.g., a droplet or roughly spherical shape) that remains in the bottomof the eye, effectively out of the patient's vision. The same is truewhen the formulation is injected into the anterior chamber of the eye.After injection into either site, the formulation steadily releasesprostaglandin to the aqueous humour in the anterior chamber of the eye,where it acts to relieve intraocular pressure. Because the dose isconstant and delivered accurately, formulations containing relativelylow amounts of drug can be used, even delivering picograms ofprostaglandin to the anterior chamber. The practitioner can observe thedosage form within the patient's eye, and prostaglandin is released aslong as the formulation is present. This allows for ease in monitoringthe medicine in relation to the intraocular pressure, and allows foraccurate dosing information. This also assists the physician inscheduling re-administration in a dosage regimen. Moreover,prostaglandin levels can be adjusted by adjusting the size of the unitdose or the concentration of the prostaglandin in the dose. A specificembodiment consisting of latanoprost in benzyl benzoate is an injectableliquid formulation.

In a particular embodiment, the present invention provides for amedicament for the treatment of elevated intraocular pressure orglaucoma, the medicament consisting of 0.1% to 5% (w/w %), inclusive, ofa prostaglandin in benzyl benzoate, for intravitreal injection in adosing regimen that consists of injecting into the vitreous of the eye adosage volume of the medicament ranging from 5 μL to 60 μL, inclusive,no more frequently than once every two months.

DESCRIPTION OF DRAWINGS

FIG. 1 shows the in vivo release profiles of latanoprost (pg/mL) fromthree formulations of latanoprost in benzyl benzoate (Lat/BB)administered as a single, 50 μL injection. y-axis: concentration oflatanoprost acid in the aqueous humour (pg/mL); x-axis: days; ♦1% (w/w%) Lat/BB; ▪2% Lat/BB; ▴4% Lat/BB.

FIG. 2 shows the in vivo release profiles of latanoprost (pg/mL) fromthree formulations of latanaprost in benzyl benzoate administered as asingle, 30 μL injection. y-axis: concentration of latanoprost acid inthe aqueous humour (pg/mL); x-axis: days; ♦1% Lat/BB (w/w %); 2% Lat/BB;4% Lat/BB.

FIG. 3 compares in vivo release profiles of latanoprost (ng/mL) fromthree formulations of 1%, 2% or 4% latanoprost (% Lat w/w) in benzylbenzoate; administered as a single, 50 μL intravitreal injection intorabbit eyes. Samples of the humour of the anterior chamber (AC) andvitreous humour were collected on the days indicated. y-axis:concentration of latanoprost acid in the sample; x-axis: days; ▪1% LatAC levels; □1% Lat vitreous levels; ▴2% Lat AC levels; Δ2% Lat vitreouslevels; 4% Lat AC levels; ∘4% Lat vitreous levels.

FIG. 4 compares the weekly intraocular pressure (IOP [mm hg]) ofrabbits' untreated eyes (♦) with eyes injected with 50 μL of 1% (w/w %)latanoprost in benzyl benzoate (▪) over the course of 22 weeks.

FIG. 5 compares the weekly intraocular pressure (IOP [mm hg]) ofuntreated eyes (♦) with eyes injected with 50 μL of 2% (w/w %)latanoprost in benzyl benzoate (▪) over the course of 22 weeks.

FIG. 6 compares the weekly intraocular pressure (IOP [mm hg]) ofuntreated eyes (♦) with eyes injected with 50 μL of 4% (w/w %)latanoprost in benzyl benzoate (▪) over the course of 28 weeks.

DETAILED DESCRIPTION

All patents and other publications identified are expressly incorporatedherein by reference for the purpose of describing and disclosing, forexample, the methodologies described in such publications that might beused in connection with the present invention. These publications areprovided solely for their disclosure prior to the filing date of thepresent application. Nothing in this regard should be construed as anadmission that the inventors are not entitled to antedate suchdisclosure by virtue of prior invention or for any other reason. Allstatements as to the date or representation as to the contents of thesedocuments are based on the information available to the applicants anddoes not constitute any admission as to the correctness of the dates orcontents of these documents.

As used herein and in the claims, the singular forms include the pluralreference and vice versa unless the context clearly indicates otherwise.The term “or” is inclusive unless modified, for example, by “either.”Other than in the operating examples, or where otherwise indicated, allnumbers expressing quantities of ingredients or reaction conditions usedherein should be understood as modified in all instances by the term“about.”

Unless otherwise defined, scientific and technical terms used inconnection with the formulations described herein shall have themeanings that are commonly understood by those of ordinary skill in theart. The terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to limit the scope ofthe present invention, which is defined solely by the claims.

The major risk factor for most glaucomas, and focus of treatment, isincreased intraocular pressure, i.e., ocular hypertension. Intraocularpressure is a function of production of liquid aqueous humour by theciliary processes of the eye, and its drainage through the trabecularmeshwork. Aqueous humour flows from the ciliary processes into theposterior chamber, bounded posteriorly by the lens and the zonules ofZinn, and anteriorly by the iris. It then flows through the pupil of theiris into the anterior chamber, bounded posteriorly by the iris andanteriorly by the cornea. From there, the trabecular meshwork drainsaqueous humour via Schlemm's canal into scleral plexuses and generalblood circulation.

Eye pressure is measured in millimeters of mercury (mm Hg). Normal eyepressure ranges from 12-22 mm Hg, and eye pressure of greater than 22 mmHg is considered higher than normal.

In open/wide-angle glaucoma, flow is reduced through the trabecularmeshwork, due to the degeneration and obstruction of the trabecularmeshwork, whose original function is to absorb the aqueous humour. Lossof aqueous humour absorption leads to increased resistance and thus achronic, painless buildup of pressure in the eye. In close/narrow-angleglaucoma, the iridocorneal angle is completely closed because of forwarddisplacement of the final roll and root of the iris against the cornea,resulting in the inability of the aqueous fluid to flow from theposterior to the anterior chamber and then out of the trabecularnetwork. This accumulation of aqueous humour causes an acute increase ofpressure and pain.

As noted above, the trabecular meshwork is a tiny spongy tissue thatallows fluid to leave the eye via the anterior chamber. The trabecularmeshwork is assisted to a small degree in the drainage of aqueous humourby a second outflow pathway, the uveoscleral pathway (5-10% of outflowoccurs this way). The uveoscleral pathway is increased (i.e., opened)with the use of glaucoma drugs such as prostaglandin agonists. Suchprostaglandins are used routinely in lowing intraocular pressure inopen-angle glaucoma, but these medications are also indicated inangle-closure glaucoma if a safe intraocular pressure level can not bereached after angle-opening procedures. Prostaglandins work by affectingthe aqueous drainage system within the eye to increase aqueous outflowwhich, in turn, lowers intraocular pressure (IOP). Currently, whendelivered to the eye as an eye drop, the drug goes into the anteriorchamber where it is active.

Selective prostaglandin analogs became generally available as eye dropsfor the treatment of glaucoma in 1996. These include latanoprost(marketed as Xalatan® by Pfizer), bimatoprost (prostamide analog,marketed as Lumigan® by Allergan), travoprost (fluprostenol isopropylester, available from Cayman Chemical, Ann Arbor, Mich.; marketed asTravatan Z® by Alcon), unoprostone (marketed as Rescula® by SucampoPharma Americas, Inc.), tafluprost (marketed as Zioptan™ by Merck),prostaglandin E₁ (alprostadil), and prostaglandin E₂ (dinoprostone).Other prostaglandin analogs for medicinal use include cloprostenol. Seealso WO/2011/046569, Process for the preparation of F-seriesprostaglandins.

Thus, as used herein, the term “prostaglandin” includes FP-receptoragonists, prostamide receptor agonists, prostaglandins, prostaglandinanalogs, prostamides, prostamide analogs, and pro-drugs and activemetabolites of these. In specific embodiments, the prostaglandin islatanoprost. Because the prostaglandins are similar in chemicalstructure, it is expected that one skilled in the art can formulatethese drugs in benzyl benzoate (and benzyl benzoate equivalents) asdescribed herein without undue experimentation.

Latanoprost and travoprost are actually prostaglandin prodrugs (i.e.,1-isopropyl esters of a prostaglandin) but they are referred to asprostaglandins because they act on the prostaglandin FP-receptor afterbeing hydrolyzed to the 1-carboxylic acid. Latanoprost is currentlyavailable in a generic form. In the eye, latanoprost is rapidlyhydrolyzed to the active form, latanoprost acid, by endogenous esteraseenzymes. Its chemical name isisopropyl-(Z)7[(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate.Its molecular formula is C₂₆H₄₀O₅, molecular weight432.58, and itschemical structure is:

Latanoprost is a colorless to slightly yellow oil that is very solublein acetonitrile and freely soluble in acetone, ethanol, ethyl acetate,isopropanol, methanol, and octanol. It is practically insoluble inwater. Latanoprost and other prostaglandin analogs are availablecommercially, for example, from Cayman Chemical (Ann Arbor, Mich.).

Particular formulations embodied herein provide for liquid latanoprostin the liquid excipient benzyl benzoate. Benzyl benzoate is abiocompatible, biodegradable, bioerodible, low solubility excipient thatprovides for a conveniently injectable sustained release formulation formany active agents. Other benzoates that are envisioned for use in placeof or with benzyl benzoate include ethyl benzoate, n-propyl benzoate,isopropyl benzoate, n-butyl benzoate and isobutyl benzoate. See U.S.Pat. No. 7,906,136; U.S. Patent Publication No. 2008/0038316. Use ofthis single, liquid excipient is advantageous over complex polymers usedcurrently in other sustained release devices and formulations. Thepresent formulations are configured to release the latanoprost forextended periods of time at relatively steady rates compared tocommercially available eye drop formulations. In some embodiments, thelatanoprost is released at a substantially linear rate (e.g., a singlerate) over many weeks or months (i.e., until the monolithic dosage formdegrades).

When the prostaglandin/benzyl benzoate liquid formulation is injectedslowly into the vitreous or anterior chamber of the eye, monolithicintegrity is maintained and a uniform liquid reservoir is formed. Thisliquid reservoir maintains its integrity and in vivo “breakage” has notbeen observed ophthalmoscopically. In other words, the formulation doesnot break up as a multitude of smaller droplets or particles thatmigrate away from the intended point of placement or by virtue of aresultant increase in surface area greatly alter the intended releaserate of the drug content. The dosage form is placed in the eye where itdoes not obscure patient vision. The dosage form can be observed in theeye by the physician, however, and as long as the formulation is visiblein the eye the prostaglandin is being released. None of the compositionremains at the end of therapy, which facilitate the administration ofadditional doses, as most major ophthalmic diseases are chronic innature.

In particular embodiments, the liquid formulations are, for example,0.1% 0.25%, 0.5%, 1%, 2%, 3%, 4%, or 5% (w/w %) equivalent latanoprost,inclusive, in benzyl benzoate. In other words, example weight ratios oflatanoprost:benzyl benzoate of the formulations described herein can be,for example, 0.1:99.9, 0.25:99.75, 0.5:99.5, 1:99, 2:98, 3:97, 4:96, or5:95, or ranges in between, such as 2.5:97.5 latanoprost:benzyl benzoate(w:w).

Unit dose sizes for injection into the vitreous or anterior chamber aregenerally in the range of 5 μL to 60 μL, inclusive; and typically in therange of 20 μL to 40 μL, inclusive. Volumes equal to or larger than 100μL are typically not injected into the eye, but in some instancesvolumes in excess of 100 μL may be warranted. Thus, for example, unitdosage volumes in some embodiments can be about 5 μL, 10 μL, 20 μL, 25μL, 30 μL, 40 μL, 50 μL, 60 μL, 70 μL, 80 μL, 90 μL, or 100 μL, or avolume included within this range. A particular dosage form or unitconsists of about 20 μL to 25 μL of a concentration selected from 0.1%to 1.0% latanoprost (w/w), inclusive, in benzyl benzoate, such as adosage form consisting of about 25 μL of 0.5% latanoprost in benzylbenzoate.

Additionally, the w/w % may be adjusted according to the nature of thelatanoprost source and reflect volume, percentage and weight of aformulation. For example, a unit dosage may be expressed as 20 μL of 1%latanoprost intravitreal injection, 224 μg equivalent latanoprost dose;50 μL of 1% latanoprost intravitreal injection, 559 μg equivalentlatanoprost dose; 20 μL of 2% latanoprost intravitreal injection, 447 μgequivalent latanoprost dose; 50 μL of 2% latanoprost intravitrealinjection, 1118 μg equivalent latanoprost dose; 20 μL of 4% latanoprostintravitreal injection, 894 μg equivalent latanoprost dose; or 50 μL of4% latanoprost intravitreal injection, 2236 μg equivalent latanoprostdose; or the like.

A syringe apparatus including an appropriately sized needle, forexample, a 22 gauge needle, a 27 gauge needle, or a 30 gauge needle, canbe effectively used to inject the formulation into the vitreous oranterior chamber of the eye. Frequent repeat injections are often notnecessary due to the sustained release of the latanoprost from theformulation. The injection process is standard and relatively fast, anddoes not require additional surgical procedures. The accuracy indelivery of small volumes to the eye may be aided by use of a dose guidefor an injection syringe, for example, as taught in publication WO2012/149040.

Specific example unit dose formulations of latanoprost (w/w %) in benzylbenzoate include 5 μL 1% latanoprost; 20 μL to 25 μL 0.1% latanoprost;20 μL to 25 μL 0.25% latanoprost; 20 μL to 25 μL 0.5% latanoprost; 20 μLto 25 μL 1% latanoprost; 30 μL 0.5% latanoprost; 30 μL 1% latanoprost;30 μL 2% latanoprost; 30 μL 4% latanoprost; 50 μL 0.5% latanoprost, 50μL 1% latanoprost (558 μg/50 μL); 50 μL 2% latanoprost (1118 μg/50 μl);and 50 μL 4% latanoprost (2236 μg/50 μl). One skilled in the artappreciates that there may be some minor variations in the unit dosevolume without deviating from the embodiments of the invention, and thatthe sustained release of the latanoprost is achieved.

The formulations of the present invention can be easily injected intothe anterior chamber, posterior segment, vitreous, or vitreous chamberof the eye. By injecting the prostaglandin-containing formulation intothe posterior segment of an eye, it is believed that the prostaglandin(e.g., latanoprost) is effective to enhance aqueous humour flow therebyreducing intraocular pressure. Without being bound by theory,intravitreal administration may be particularly advantageous in treatingglaucoma because it takes advantage of the eye's natural fluid flow: thevitreous humour delivers the prostaglandin to the trabecular meshworkand uveoscleral pathway as it flows to the anterior chamber. Thisprovides for delivery of the active agent to the site of action withinthe eye. By contrast, in subconjunctival administration such asimplantation or injection within the anterior sub-tenon space of theeye, the active agent must pass through the sclera of the eye.Similarly, eye drops are notoriously inefficient at delivering agent tothe anterior chamber: in current commercial glaucoma eye drops, only 1%of the active agent penetrates the tissues against the outward flow andpressure of the anterior chamber.

Dosing regimens include one injection of a prostaglandin (such aslatanoprost) in benzyl benzoate once every two months (about every 60days or 8 weeks), once every three months (about every 90 days or 12weeks), once every four months (about every 120 days or 16 weeks), onceevery five months (about every 150 days), once every six months (aboutevery 180 days), once every seven months (about every 210 days), onceevery eight months (about every 240 days), once every nine months (aboutevery 270 days), once every ten months (about every 300 days), onceevery eleven months (about every 330 days), or once every twelve months(about every 360 or 365 days, or every 52 weeks), or at periods withinthese months, weeks, or days as determined by the prescribing physicianin monitoring intraocular pressure and disease state. In commercialpractice, treatment regimens may likely be adjusted by dose volume sizeor time between injections, rather than prostaglandin concentration, butin any event will not require intravitreal injection more frequentlythan once every two months.

The formulations presented herein can also be administered with othertherapy approaches to treating an ocular condition, for example,administering additional therapeutic agents to the eye, such as bytopically administering compositions containing a carbonic anhydraseinhibitor (e.g., brinzolamide or dorzolamide) or a beta-adrenergicreceptor antagonist (e.g., timolol). These additional therapies may beadministered as eye drops, sustained release eye drops (see, e.g., U.S.Pat. No. 8,541,413), implants or ocular injections into, for example,the subconjunctiva, periocular space, retrobulbar in the orbit,episclera, intracomea, intrasclera, anterior chamber, anterior segment,posterior chamber, posterior segment, vitreous cavity, subretinal space,suprachorodial segment or intraretinal area of the eye (see, e.g., U.S.Pat. No. 7,906,136) as are known in the art.

EXAMPLES Example 1 In vivo Release of Latanoprost from Benzyl Benzoate

Liquid formulations of latanoprost and benzyl benzoate were made byweighing each component and mixing them together. Latanoprost is solublein benzyl benzoate, yielding a clear solution. The formulations wereeither 1%, 2%, or 4% (w/w %) latanoprost.

Either 30 μL or 50 μL of each formulation was injected only once intothe posterior segment of the eyes of rabbits (five rabbits performulation per dosage size; thirty rabbits). Weekly, the aqueous humourof treated eyes was collected, generally about 100 μL to 150 μL involume, pooled, concentrated 10-fold, and analyzed by liquidchromatography-mass spectrometry (LCMS) to afford the level oflatanoprost acid (the active form of the drug) released into the aqueoushumour. The concentration of the latanoprost (pg/mL) in the samples ofaqueous humour from the single, 50 μL intravitreal injection are shownin FIG. 1. The concentration of the latanoprost (pg/mL) in the samplesof aqueous humour from the single, 30 μL intravitreal injection areshown in FIG. 2. In each test, including the single injection of 30 μL1% latanoprost, latanoprost was detected in the aqueous humour in aconcentration of at least 10 pg/mL for at least 60 days.

In another in vivo experiment, formulations of either 1%, 2%, or 4% (w/w%) latanoprost in benzyl benzoate were prepared. A dose of 50 μL of eachformulation was injected only once into the posterior segment/vitreous(i.e., intravitreal injection) of the eyes of test rabbits. Thereafter,samples were collected from the aqueous humour from the anterior chamberand from the vitreous humour, and were analyzed for latanoprost acid asdescribed above. As shown in FIG. 3, even the lowest concentration oflatanoprost (1% w/w %) exhibited sustained release into the anteriorchamber of the eye for at least sixty days (two months). One skilled inthe art can readily extrapolate a sustained release profile from theseFigures.

Example 2 Intraocular Pressure Reduction

To assess the effect on intraocular pressure, five rabbits were used per1%, 2% or 4% latanoprost/benzyl benzoate formulation, and 50 μL aliquotswere injected into the posterior segment of only the left eye of eachanimal. The right eyes were not treated, and served as control. Eachweek, each eye's intraocular pressure was measured using an iCareTonometer 5x. Measurements were averaged for each time point. As shownin FIGS. 4-6, at almost all time points the intraocular pressure in thetreated eyes was lower than the pressure in the untreated eyes, even 154days after the single injection. Overall, intraocular pressure remainedlower in the treated eye compared with the untreated eyes for 196 daysin the rabbits treated with 50 μL 4% latanoprost.

Additionally, three-month toxicology reports indicated that none of thelatanoprost/benzyl benzoate formulations had any toxic effect in theeyes or bodies of the rabbits.

Example 3 Sustained Release Prostaglandin Formulations

The present prostaglandin benzyl benzoate formulations for intravitrealinjection are used in the treatment patients with open-angle glaucoma,pseudoexfoliative glaucoma, pigmentary glaucoma, or ocular hypertension.Dose escalation in a clinical trial setting is used to determine theoptimal concentration for commercial production. For example, 5 μL of a1% latanoprost represents a starting dose; and the concentration orvolume or both are stepped-up as required to determine the optimalconcentration of latanoprost that achieves the desired clinical outcome(e.g., safety, pharmacokinetic, and pharmacodynamic parameters) over astudy population, as confirmed in a randomized clinical study. Themaximum concentration envisioned herein is about 5% latanoprost (w/w %)and the maximum dose volume is about 100 μL. For example, an effectivedose for intravitreal injection no more frequently than once every twomonths may be between 20 μL to 60 μL of latanoprost in a concentrationrange between 0.1% and 4% (w/w %), inclusive, such as about 25 μL of0.50% latanoprost. It is likely that a commercially relevantconcentration is determined, and thereafter a dosing regimen isrecommended based on adjusting dose volume and frequency of injections.For example, the formulation as initially administered may bere-administered once the preceding dose is no longer visible byphysician, depending on therapeutic outcome. Moreover, one skilled inthe art is aware that the pharmacological effect of the treatment maylast beyond the time at which the sustained release formulation hasfully bioeroded.

Further regarding dose and administration, the intravitreal injection ofsustained release prostaglandin is carried out under aseptic conditions,using sterile drape, sterile gloves, and sterile eyelid speculum. Undercurrent best practices, proper anesthesia and povidone-iodine areadministered before the injection. During the injection, the physicianwears a surgical mask. After injection, the patient is monitored forintraocular pressure. Ocular examination by indirect ophthalmoscopicexamination is performed following the injection of drug. The patient isinstructed to report any symptoms of pain or redness suggestive of aninfection (endophthalmitis) immediately to their ophthalmologist.

Efficacy outcome measure include intraocular pressure (IOP) is currentlythe accepted standard for establishing the efficacy of ocularhypotensive medications. IOP is a surrogate end point for potentialvisual function loss. For equivalence trials efficacy is attained if thedifference in mean TOP between treatment groups is within ±1.50 mm Hg atall post-baseline time points; and within ±1.00 mm Hg at the majority ofpost-baseline time points. This regulatory requirement for equivalencehas been consistently used for the approval of several IOP loweringproducts over many years.

We claim:
 1. A liquid medicament for use in the treatment of elevatedintraocular pressure or glaucoma in a subject, the medicament consistingof prostaglandin in benzyl benzoate, the prostaglandin present at about0.1% (w/w) to about 5% (w/w), inclusive, the medicament for a dosingregimen in which about 5 μL to about 60 μL, inclusive, is injected intothe anterior chamber or vitreous of the eye once per interval of no lessthan about two months.
 2. The medicament of claim 1, wherein the liquidmedicament is injected once per interval of no less than about threemonths.
 3. The medicament of claim 2, wherein the liquid medicament isinjected once per interval of no less than about six months.
 4. Themedicament of claim 1, wherein the prostaglandin is latanoprost.
 5. Themedicament of claim 4, wherein the liquid medicament is from about 20 μLto about 25 μL, inclusive, and the medicament contains latanoprost at aconcentration of about 0.1% (w/w) to about 1% (w/w), inclusive.
 6. Themedicament of claim 5, wherein the liquid medicament is injected onceper interval of no less than about two months.
 7. The medicament ofclaim 5, wherein the liquid medicament is injected once per interval ofno less than about three months.
 8. The medicament of claim 5, whereinthe liquid medicament is injected once per interval of no less thanabout six months.
 9. A sustained release unit dose for treating elevatedintraocular pressure or glaucoma in a subject, wherein the unit dose isa liquid consisting of latanoprost at a concentration of about 0.25%(w/w) to about 5% (w/w), inclusive, in benzyl benzoate, wherein the unitdose is about 5 μL to about 60 μL, inclusive, is administered byintravitreal injection, and optionally thereafter is re-administered nomore frequently than once about every two months.
 10. The sustainedrelease unit dose as in claim 9, wherein the unit dose containslatanoprost at about 0.1% (w/w) to about 1% (w/w), inclusive, andoptionally is re-administered no more frequently than once about everythree months.
 11. The sustained release unit dose as in claim 9, whereinsaid unit dose is about 20 μL of about 1% (w/w) latanoprost in benzylbenzoate and is equivalent to about 224 μg of latanoprost dose.
 12. Thesustained release unit dose as in claim 9, wherein said unit dose isabout 50 μL of about 1% (w/w) latanoprost in benzyl benzoate and isequivalent to about 559 μg of latanoprost dose.
 13. The sustainedrelease unit dose as in claim 9, wherein said unit dose is about 20 μLof about 2% (w/w) latanoprost in benzyl benzoate and is equivalent toabout 447 μg of latanoprost dose.
 14. The sustained release unit dose asin claim 9, wherein said unit dose is about 50 μL of about 2% (w/w)latanoprost in benzyl benzoate and is equivalent to about 1118 μg oflatanoprost dose.
 15. The sustained release unit dose as in claim 9,wherein said unit dose is about 20 μL of about 4% (w/w) latanoprost inbenzyl benzoate and is equivalent to about 894 μg of latanoprost dose.16. The sustained release unit dose as in claim 9, wherein said unitdose is about 50 μL of about 4% (w/w) latanoprost in benzyl benzoate andis equivalent to about 2236 μg of latanoprost dose.
 17. The sustainedrelease unit dose as in claim 9, wherein said unit dose is expressed asabout 224 μg, 447 μg, 559 μg, 894 μg, 1118 μg, or about 2236 μgequivalent latanoprost dose.